In the medical field there is a continuing need for new compounds having demonstrated use for inducing anesthesia. It is not only important to induce beneficial anesthesia, but it must be done in a manner that limits toxicity to patients, and as well, minimizes what is known as “anesthesia hangover”.
The pineal hormone melatonin (N-acetyl-5-c) has several putative functions, including regulation of circadian rhythms, regulation of the reproductive axis and antioxidant activity. Autoradiographic studies and receptor assays have demonstrated the presence of melatonin receptors in various regions of the central nervous system and in other tissues in humans.
Exogenous administration of melatonin has been found by several investigators to facilitate sleep onset and improve quality of sleep. Available data suggest that the sleep-inducing properties of melatonin may differ from those of benzodiazepines. Benzodiazepines decrease duration of REM sleep after single administration of a high dose or long-term administration of low dose. Benzodiazepines also reduce slow-wave sleep, thus negatively influencing sleep quality. In contrast, a single low dose of melatonin produced no suppression of REM sleep. Furthermore, unlike benzodiazepines, melatonin does not induce “hangover” effects.
In a previous publication of one of the inventors, British Journal of Anesthesia 82(6): 875-80(1999), low-level dosing of oral melatonin in a sublingual fashion was demonstrated as an effective pre-medication, prior to administering a general anesthetic. Patients who were administered such low-level doses sublingually had a significant decrease in anxiety levels and an increase in levels of sedation before operation. However, as pointed out in that article, the use of melatonin in anesthesia had as of then never been evaluated properly, and to the inventor's present knowledge it has never been used as a general anesthetic prior to this series of applications.
The invention of our U.S. Pat. No. 6,522,064 had as its primary objective the development of pineal hormone melatonin (N-acetyl-5-methoxytryptamine) or its biologically active analogues as a general anesthetic which can be used without any significant anesthetic hangover. The continuing need in the art for meeting that objective was readily apparent.
With reference to the continuing need referred to above, applicants continued to work with melatonin and its analogues to derive improved compounds which may be used for anesthetic effect generally and in small doses for hypnotic effect sedation or even sleep inducement. This continuing work evolved into the discovery that 2-trihalo methyl melatonins and in particular the 2-trifluoromethylmelatonin are substantially more active in anesthetic effect than melatonin itself. The result of this increased activity meant that the compounds may be used in larger doses for general anesthesia, but in smaller doses for hypnotic effect and sedation and sleep effect.
Further discoveries since the filing of the original application have revealed a particularly effective pharmaceutical carrier for melatonin, melatonin analogues and the improved derivatives of the present invention. The carrier allows dissolving and high concentrations of melatonin or its analogues. The preferred carrier is comprised of one volume of 1-methyl-2-pyrrolidinone, one volume of propylene glycol and two volumes of water. It goes without saying that the volumetric ratios of these carrier solvents may be varied somewhat, depending upon the circumstances. These discoveries resulted in our U.S. Pat. No. 6,638,966.
Because melatonin and the melatonin analogues of our previous patents are somewhat difficultly soluble in aqueous vehicles, the Applicants have continued their efforts to find active analogues which could be administered with aqueous vehicles.
Disclosed here are prodrugs of melatonin analogues which can be administered preferentially in aqueous vehicles. Melatonin is a water-insoluble compound that cannot be administered to patients by injection using an aqueous vehicle. Furthermore, melatonin can not be formulated into an organic solvent that is free of side effects. For example, organic solvents such as ethanol, N-methyl-pyrrolidione, ethyl acetate, tetrahydrofuran, and propylene glycol, will solublize melatonin; however, these solvents are either toxic to the patient, have undesirable side-effects, or they are not approved for administration to humans by parenteral administration. Melatonin also cannot be administered in an oil-in-water emulsion because it is poorly soluble in oils that can be made into oil-in-water emulsions, such as soybean, safflower, or olive oil.
It is therefore desired to have a compound, which exerts the beneficial effects of melatonin including anti-oxidation, sedation, anesthesia, protection of organs to chemical, infectious and cardiovascular damage, and can be administered in a water-based or aqueous vehicle. This invention fulfills this desire or need.